Combination therapy for prostate cancer

Abstract

The application relates to a combination therapy for prostate cancer. The present invention provides methods and compositions for treating prostate cancer by administering to a patient in need thereof: a therapeutically effective amount of a PARP inhibitor, such as niraparib; a therapeutically effective amount of a CYP17 inhibitor, such as abiraterone acetate; and a therapeutically effective amount of a glycocortin, such as prednisone.

Description

[0001] This application is a divisional application of an invention patent application with an application date of October 18, 2018, application number 201880039365.1 (PCT / US2018 / 026661), and invention name “Combination therapy for prostate cancer”. Technical Field

[0002] The present disclosure relates to the use of small molecule therapeutics for treating prostate cancer. Background Art

[0003] Prostate cancer is the second leading cause of death of men because of cancer in the modal non-skin malignancy and western world in men. Prostate cancer is caused by the uncontrolled growth of abnormal cells in the prostate. Once prostate cancer tumor develops, androgens such as testosterone promote prostate cancer growth. In its early stage, localized prostate cancer is usually treated with local therapy, including, for example, surgical removal of the prostate and radiotherapy for curing. However, when local therapy can not cure prostate cancer, the incurable male of this therapy is up to 1 / 3rd, and the disease develops into incurable metastatic disease (that is, cancer spreads to the disease of other positions from one position of the body).

[0004] For many years, the established standard of care for men with mCRPC has been docetaxel chemotherapy. More recently, abiraterone acetate has been used to treat mCRPC. Combination with prednisone has been shown to be effective in the treatment of metastatic castration-resistant prostate cancer. Androgen receptor (AR) targeted drugs such as enzalutamide It is also on the market for the treatment of metastatic castration-resistant prostate cancer. Platinum-based chemotherapy has been tested in multiple clinical studies in patients with molecularly unselected prostate cancer, but the results are limited and the toxicity is significant. However, there is still a subset of patients who do not initially respond or become refractory (or resistant) to these treatments. There are no approved treatment options for these patients.

[0005] Niraparib (2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide) is an orally available, highly selective poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor that is active against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. (Jones P, Wilcoxen K, Rowley M, Toniatti C. Niraparib: APoly(ADP-ribose)Polymerase(PARP)Inhibitor for the Treatment of Tumors with Defective Homologous Recombination. J Med Chem. 2015 Apr 23;58(8):3302-3314).

[0006] PARP is an enzyme responsible for repairing DNA single-strand breaks (SSBs) through a process known as base excision repair. PARP inhibition leads to the accumulation of unrepaired SSBs, which leads to the stagnation and collapse of replication forks and, therefore, double-strand breaks (DSBs). Typically, DSBs are repaired by homologous recombination (HR). If they cannot be repaired, DSBs can lead to cell death. When tumor cells with DNA repair defects involving the HR pathway (e.g., breast cancer gene [BRCA]-1 / 2) are treated with PARP inhibitors, they are unable to effectively and accurately repair DSBs, which will produce synthetic lethal conditions. In men with metastatic castration-resistant prostate cancer (mCRPC), tumors with DNA repair abnormalities account for approximately 20% to 30% of sporadic cancers.

[0007] Recently, the PARP inhibitor olaparib was studied in a phase 2 study to evaluate the efficacy and safety of AR-targeted agents in patients with mCRPC after chemotherapy. Gene sequencing identified homozygous deletions, deleterious mutations, or both in DNA repair genes, including but not limited to BRCA-1 / 2, ATM, Fanconi anemia genes, and CHEK2 in tumor samples. Sixteen of 49 patients responded (33%; 95% confidence interval [CI]: 20%, 48%). Response was defined as one or more of the following: objective response, circulating tumor cell (CTC) transformation, or prostate-specific antigen (PSA) decline ≤50%. Of these 16 patients, 14 (88%) responded to olaparib and were biomarker positive for abnormalities in DNA repair genes, including all 7 patients with BRCA-2 loss (4 with biallelic somatic loss and 3 with germline mutations) and 4 of 5 patients with ATM abnormalities. In contrast, only 2 of 33 biomarker-negative patient tumors (6%) responded. The radiological progression-free survival (rPFS) in the biomarker-positive group was significantly longer than that in the biomarker-negative group (median values ​​were 9.8 months and 2.7 months, respectively). The overall survival (OS) in the biomarker-positive group was also longer than that in the biomarker-negative group (median values ​​were 13.8 months and 7.5 months, respectively).

[0008] However, there remains a need for therapies that target prostate cancer, including hormone-sensitive, hormone-naïve high-risk, and castration-resistant prostate cancer. Summary of the invention

[0009] Provided herein are methods for treating prostate cancer comprising, consisting of, and / or consisting essentially of administering to a patient in need thereof a therapeutically effective amount of a PARP inhibitor, a therapeutically effective amount of a CYP17 inhibitor, and a therapeutically effective amount of a glucocorticoid.

[0010] Provided herein are methods for treating prostate cancer comprising, consisting of, and / or consisting essentially of administering to a patient in need thereof a therapeutically effective amount of niraparib, a therapeutically effective amount of abiraterone acetate, and a therapeutically effective amount of prednisone.

[0011] Provided herein are methods for treating prostate cancer comprising, consisting of, and / or consisting essentially of administering to a patient in need thereof a therapeutically effective amount of niraparib, a therapeutically effective amount of abiraterone acetate, and a therapeutically effective amount of prednisone.

[0012] Also disclosed are pharmaceutical compositions comprising, consisting of, and / or consisting essentially of niraparib, abiraterone acetate, and prednisone in a total amount that is therapeutically effective for treating prostate cancer in a human patient.

[0013] The present disclosure also provides kits comprising, consisting of, and / or consisting essentially of: a composition comprising niraparib; a composition comprising abiraterone acetate; and a composition comprising prednisone; and instructions for administering the composition to a human patient having prostate cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 The effect of niraparib and / or abiraterone on tumor volume in castrated male mice bearing VCaP tumors is shown. Mean + / - SEM is plotted. N = 10 / group. Tumors were implanted on day 0, when tumors were approximately 200 mm 3 Castration occurred on day 22, and qd dosing occurred on days 23 to 57. Note that niraparib was dosed at 31.4 mg / kg for the first 5 days of dosing and then at 50 mg / kg for the remainder of the implementation period. Abiraterone was dosed at 200 mg / kg throughout the dosing period.

[0015] Figure 2 The effect of niraparib and / or abiraterone on survival of castrated male mice with VCaP tumors is shown. N-10 / group. Tumors were implanted on day 0, castration occurred on day 22, and qd dosing occurred on days 23 to 57. Note that niraparib was dosed at 31.4 mg / kg for the first 5 days of dosing and then at 50 mg / kg for the remainder of the run period. Abiraterone was dosed at 200 mg / kg throughout the dosing period. DETAILED DESCRIPTION

[0016] The present invention may be more readily understood in conjunction with the following detailed description of the accompanying examples which form a part of this disclosure. It should be understood that these inventions are not limited to the specific products, methods, conditions or parameters described and / or shown herein, and that the terminology used herein is only used to describe specific embodiments by way of example and is not intended to limit the invention protected by the claims.

[0017] The entire disclosure of each patent, patent application, and publication cited or described in this document is hereby incorporated by reference.

[0018] As used above and throughout this disclosure, the following terms and abbreviations shall be understood to have the following meanings, unless otherwise indicated.

[0019] In this disclosure, unless the context clearly dictates otherwise, the singular forms "a," "an," "the," and "said" include plural references, and references to specific values ​​include at least that specific value. Thus, for example, reference to "an ingredient" refers to one or more of such ingredients and equivalents thereof known to those skilled in the art, and so forth. Furthermore, when it is indicated that an element "may be" X, Y, or Z, such usage is not intended to exclude other choices of the element in all cases.

[0020] When "about" is used above to express a value as an approximation, it should be understood that the specific value constitutes another embodiment. As used herein, "about X" (wherein X is a numerical value) preferably refers to the quoted value ± 10%, including the end value. For example, the term "about 8" refers to a value of 7.2 to 8.8, including the end value; as another example, the term "about 8%" refers to a value of 7.2% to 8.8%, including the end value. Where present, all ranges include the end value and are combinable. For example, when citing a range of "1 to 5", the quoted range should be understood to include ranges such as "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5". In addition, when a list of alternatives is provided affirmatively, such a list may also include embodiments in which any of the alternatives may be excluded. For example, when describing a range of "1 to 5", such description may cover the situation where any of 1, 2, 3, 4 or 5 is excluded; thus, a reference to "1 to 5" may cover "1 and 3 to 5, but not including 2", or simply "wherein 2 is not included".

[0021] definition

[0022] As used herein and unless otherwise defined, the terms "treat," "treating," and "treatment," "treating," and "therapy" include eradicating, eliminating, altering, managing, or controlling tumors or primary, localized, or metastatic prostate cancer cells or tissue, as well as minimizing or delaying the spread of prostate cancer.

[0023] As used herein and unless otherwise defined, the phrase "therapeutically effective amount" refers to an amount of a therapeutic agent that is effective for treating prostate cancer.

[0024] As used herein and unless otherwise defined, the phrase "therapeutically safe" refers to an amount of a therapeutic agent that is effective for treating prostate cancer.

[0025] The present disclosure relates particularly to methods for treating prostate cancer, comprising administering to a patient in need thereof a therapeutically effective amount of niraparib, abiraterone acetate, and prednisone. As described above, current treatment options for improving survival and limiting progression in men with metastatic castration-resistant prostate cancer (mCRPC) include taxane-based chemotherapy and androgen receptor targeted drugs such as apalutamide and enzalutamide. However, there remains a subset of patients who do not initially respond or become refractory to these treatments. There are no approved treatment options for these patients.

[0026] In response to genotoxic insults, poly (adenosine diphosphate [ADP] -ribose) polymerase (PARP) recruits proteins that promote DNA repair. In addition to promoting DNA repair, recent studies have also observed a dual role for PARP in supporting androgen receptor activity. That is, models of CRPC show a significant upregulation of PARP activity. Therefore, PARP inhibition in preclinical models enhances the anti-tumor effect of castration and delays the onset of castration resistance. In addition, primary human prostate tumor in vitro cultures showed a significant anti-tumor response to PARP inhibition, which was associated with reduced androgen receptor activity. Similarly, in preclinical models, a significant decrease in the survival of cells treated with anti-androgens, bicalutamide and ATM inhibitors was observed in colony formation assays when compared to regimens treated with bicalutamide or ATM inhibitors alone. Considering that the androgen receptor is still able to transmit signals after castration therapy in CRPC, the inventors determined the primary role of the potential synergistic effect of PARP inhibition and androgen receptor antagonism.

[0027] Niraparib, shown below, is an orally available, highly selective poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor that has potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases.

[0028]

[0029] The preparation of niraparib (2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide) is described in U.S. Patents 8,071,623 and 8,436,185, both of which are incorporated herein by reference. Niraparib is currently being studied for the treatment of ovarian, breast, and prostate tumors in patients with DNA repair abnormalities.

[0030] In cancer cell lines that have been silenced for BRCA-1 or BRCA-2 or that have mutations in both BRCA-1 and BRCA-2, niraparib exhibits antiproliferative activity due to cell cycle arrest followed by apoptosis. In addition, in vivo studies in mice have shown that niraparib has antitumor activity against BRCA-1-deficient breast cancer, BRCA-2-deficient pancreatic cancer, and ovarian cancer.

[0031] Niraparib is not an effective inhibitor or inducer of cytochrome P450 (CYP) enzymes; therefore, it is considered to have a low probability of causing drug interactions (DDI). However, preclinical data show that niraparib has a moderate probability of inducing CYP1A2 enzymes. Niraparib is a low clearance drug, and limited metabolism has been observed in vitro with the participation of multiple metabolizing enzymes (both CYP and non-CYP). Therefore, when co-administered with regulators of CYP enzymes, significant changes in niraparib pharmacokinetics (PK) are not expected. Niraparib is a P-glycoprotein substrate. In animal studies, niraparib was observed to be distributed to the central nervous system (CNS); however, in CNS safety studies using conscious mice, niraparib had no effect on neurological function. For anesthetized dogs, the QTc interval was not affected; however, mean arterial pressure, heart rate, and QRS heart interval increased. In repeated dose toxicity studies in rats and dogs, hematological toxicity was observed, but was resolved at the end of the recovery period (usually 15 to 28 days).

[0032] Although niraparib is preferred, it is contemplated that any PARP inhibitor may be used in the present invention, such as talazopanib, rucaparib, olaparib, iniparib, talazopanib, and veliparib. Abiraterone acetate (available under the trade name niraparib) is shown below. Obtained from the European Medicines Agency (EMA), it is a 17a-hydroxylase / C17,20-lyase (CYP17) inhibitor that blocks androgen biosynthesis in testicular, adrenal, and prostate tumors.

[0033]

[0034] Abiraterone acetate, the active metabolite of abiraterone, inhibits CYP17A1 by inhibiting two enzymes, 17α-hydroxylase (IC 50=2.5nM) and 17,20-lyase (IC50=15nM) (six-fold selectivity for inhibiting 17α-hydroxylase over 17,20-lyase), which are expressed in testis, adrenal glands, and prostate tumor tissues. CYP17 catalyzes two sequential reactions: (1) conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives via its 17α-hydroxylase activity, and (2) subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, via its 17,20-lyase activity. DHEA and androstenedione are androgens and precursors of testosterone. Thus, inhibition of CYP17 activity by abiraterone reduces circulating levels of androgens such as DHEA, testosterone, and dihydrotestosterone (DHT).

[0035] Administration of abiraterone acetate has the ability to reduce circulating testosterone levels to less than 1 ng / dL (i.e., undetectable), and these concentrations are much lower than those achieved with castration (20 ng / dL). It was found that the effect of adding administration of abiraterone acetate to castration reduced DHT levels by 85%, DHEA levels by 97% to 98%, and androstenedione levels by 77% to 78%, relative to castration alone.

[0036] Niraparib and abiraterone acetate may also be administered in combination with steroids such as corticosteroids or glucocorticoids. Niraparib and abiraterone acetate and the steroid may be administered in the same or different compositions. Non-limiting examples of suitable steroids include hydrocortisone, prednisone, prednisolone, methylprednisolone, or dexamethasone. The amount of steroid administered is an amount sufficient to treat prostate cancer, whether administered alone or in combination with niraparib and abiraterone acetate.

[0037] In one embodiment, provided herein are methods and compositions comprising niraparib, abiraterone acetate and a steroid (specifically a corticosteroid, or more specifically a glucocorticoid). Steroids within the scope of the present disclosure include, but are not limited to (1) hydrocortisone (cortisol; cypionate (e.g., CORTEF), oral; sodium phosphate injection (hydrocortisone sodium phosphate); sodium succinate (e.g., hydrocortisone sodium succinate, steroid); cortisone acetate oral or injection form, etc.), (2) dexamethasone (dexamethasone) (e.g., dexamethasone (Decadron), oral; dexamethasone-LA injection, etc.), (3) prednisolone (e.g., prednisolone, prednisolone acetate (ECONOPRED), prednisolone sodium phosphate (HYDELTRASOL), prednisolone butyrate (HYDELTRA-TBA, etc.)), or (4) prednisone (DELTASONE, etc.) and combinations thereof. See, for example, GOODMAN and GILMAN, THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 10th edition, 2001.

[0038] In a specific embodiment, a single unit solid oral dosage form is contemplated, comprising in a single composition an amount of abiraterone acetate in the range of about 50 mg to about 300 mg and an amount of a steroid, such as a glucocorticoid, in the range of about 0.5 mg to about 3.0 mg, and optionally an excipient, carrier, diluent, etc. For example, a single unit dosage form may comprise about 250 mg of abiraterone acetate and about 1.0 mg, 1.25 mg, 1.5 mg, or 2.0 mg of a steroid, such as, but not limited to, a corticosteroid or a glucocorticoid.

[0039] Abiraterone acetate is indicated for use in combination with prednisone for the treatment of metastatic castration-resistant prostate cancer.

[0040] According to the method of the present invention, the patient to whom niraparib, abiraterone acetate and prednisone are administered may suffer from hormone-sensitive prostate cancer, hormone-unactivated localized high-risk prostate cancer or castration-resistant prostate cancer. Most but not all prostate cancers are adenocarcinomas, and the patient may suffer from adenocarcinomas or prostate cancers based on malignant tumors. In any of these cases, prostate cancer may be metastatic.

[0041] Prior to the administration of the first dose of niraparib, abiraterone acetate, and prednisone, the patient may have received one or more other types of treatment for prostate cancer. For example, the patient may have received taxane-based chemotherapy prior to the administration of the first dose of niraparib, abiraterone acetate, and prednisone. In addition or alternatively, the patient may have received at least one first-line androgen receptor targeted therapy prior to the administration of the first dose of niraparib, abiraterone acetate, and prednisone. The time period between the end of other treatments and the administration of niraparib, abiraterone acetate, and prednisone according to the present invention may be years, months, weeks, days, one day, or less than 24 hours.

[0042] Niraparib, abiraterone acetate and / or prednisone can be administered to a patient in a single composition such as a single pill (e.g., tablet or capsule), bolus injection, etc. Alternatively, niraparib, abiraterone acetate, and prednisone can be administered to a patient separately, i.e., such that niraparib, abiraterone acetate, and prednisone are physically separated from each other prior to administration. For example, niraparib, abiraterone acetate can be administered in a first dosage form, while prednisone is administered to a patient in a separate second dosage form, or niraparib, abiraterone acetate, and prednisone can be administered in separate dosage forms. When niraparib, abiraterone acetate, and prednisone are administered separately to a patient, the time period between the respective administrations is preferably a minimal time (e.g., less than about 6 hours) or effectively zero (e.g., such as when a patient simultaneously ingests two separate dosage forms, one of which contains niraparib and the other, corresponding dosage form, contains abiraterone acetate and prednisone), but may also be about one minute, about 2 minutes, about 3 minutes, about 5 minutes, about 7 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 13 hours, about 14 hours, or about 15 hours. Pharmaceutical compositions comprising niraparib, abiraterone acetate, and prednisone, or all three, are described more fully below.

[0043] The administration of niraparib, abiraterone acetate and prednisone can be once a day. In other words, niraparib can be administered once a day, abiraterone acetate can be administered once a day, and prednisone can be administered once a day. In some cases, the once-a-day administration includes administering a single composition comprising niraparib, abiraterone acetate and prednisone to the patient once a day. In other embodiments, the once-a-day administration includes administering a single composition comprising niraparib to the patient once a day, administering a second composition comprising abiraterone acetate to the patient once a day, and administering a third composition comprising prednisone to the patient once a day. Alternatively, the once-a-day administration may include administering one or more compositions that together constitute a daily dose of niraparib to the patient during a one-day period, administering one or more compositions that together constitute a daily dose of abiraterone acetate to the patient during a one-day period, and administering two or more compositions that constitute two or more daily doses of prednisone. For example, niraparib may be administered to a patient once daily as a single composition, while abiraterone acetate is administered to a patient once daily as two or more separate dosage forms, and prednisone is administered to a patient once daily as two or more separate dosage forms. Any dosage regimen encompassed by the foregoing description is contemplated.

[0044] The amount of niraparib administered to a patient can be about 30 mg / day to about 400 mg / day, about 50 mg / day to about 350 mg / day, about 75 mg / day to about 325 mg / day, about 100 mg / day to about 300 mg / day, about 100 mg / day to about 275 mg / day, about 125 mg / day to about 250 mg / day, about 150 mg / day to about 225 mg / day, about 175 mg / day to about 225 mg / day, or about 190 mg / day to about 210 mg / day, or about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 110 mg / day, about 125 mg / day to about 250 mg / day, about 150 mg / day to about 225 mg / day, about 175 mg / day to about 225 mg / day, or about 190 mg / day to about 210 mg / day. In some embodiments, the dosage form of the present invention may be about 100 mg / day, about 110 mg / day, about 120 mg / day, about 130 mg / day, about 140 mg / day, about 150 mg / day, about 160 mg / day, about 170 mg / day, about 180 mg / day, about 190 mg / day, about 200 mg / day, about 210 mg / day, about 220 mg / day, about 230 mg / day, about 240 mg / day, about 250 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 290 mg / day, about 300 mg / day, about 310 mg / day, about 320 mg / day, about 330 mg / day, about 340 mg / day, or about 350 mg / day.

[0045] The amount of abiraterone acetate administered to a patient may be about 500 mg / day to about 1500 mg / day, about 600 mg / day to about 1300 mg / day, about 700 mg / day to about 1200 mg / day, about 800 mg / day to about 1200 mg / day, about 900 mg / day to about 1100 mg / day, about 950 mg / day to about 1050 mg / day, or about 500 mg / day. , about 600 mg / day, about 700 mg / day, about 750 mg / day, about 800 mg / day, about 850 mg / day, about 875 mg / day, about 900 mg / day, about 925 mg / day, about 950 mg / day, about 1000 mg / day, about 1025 mg / day, about 1050 mg / day, about 1075 mg / day, about 1100 mg / day, or about 1125 mg / day.

[0046] The amount of prednisone administered to a patient can be about 1 mg / day to about 25 mg / day, about 2 mg / day to about 23 mg / day, about 3 mg / day to about 20 mg / day, about 4 mg / day to about 18 mg / day, about 5 mg / day to about 15 mg / day, about 6 mg / day to about 12 mg / day, about 7 mg / day to about 11 mg / day, about 8 mg / day to about 11 mg / day, about 9 mg / day to about 11 mg / day, or can be about 1 mg / day, about 2 mg / day, about 3 mg / day. , about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 11 mg / day, about 12 mg / day, about 13 mg / day, about 14 mg / day, about 15 mg / day, about 16 mg / day, about 17 mg / day, about 18 mg / day, about 19 mg / day, about 20 mg / day, about 21 mg / day, about 22 mg / day, about 23 mg / day, about 24 mg / day, or about 25 mg / day.

[0047] The method of the present invention may include administering niraparib, abiraterone acetate and prednisone to a patient over multiple days, weeks, months or years. Preferably, the administration of niraparib and abiraterone acetate occurs once a day, and the administration of prednisone occurs twice a day. The amount of niraparib, abiraterone acetate and prednisone may be constant over time (i.e., every day), or may increase or decrease over time. For example, the amount of niraparib, abiraterone acetate and prednisone or two or all three of these administered daily may be increased or decreased after one day of administration, after several days of administration, after one week of administration, and the new dosage may be maintained for any desired time period, such as several days, weeks or months, or may be subsequently increased or decreased after a desired time interval. In this way, the method of the present invention may include increasing the dosage of niraparib (e.g., the amount of niraparib administered once a day) at least once over time. The method of the present invention may also or alternatively include increasing the dose of abiraterone acetate at least once over time (e.g., the amount of abiraterone acetate administered once a day). The method of the present invention may also or alternatively include increasing the dose of prednisone at least once over time (e.g., the total amount of prednisone administered daily). The amount increased or decreased may be expressed as a percentage, and in such cases, the amount of a single episode of increase or decrease may be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 80%, about 85%, about 90%, about 95%, about 100% or greater than about 100%.

[0048] Described herein are methods for treating cancer, wherein a therapeutically effective amount of a PARP inhibitor (such as niraparib), a 17α-hydroxylase / C17,20-lyase inhibitor (such as abiraterone acetate (i.e., 3β-acetyl-17-(3-pyridyl)androsta-5,16-diene)), and a glucocorticoid (such as prednisone, prednisolone, hydrocortisone, methylprednisolone, and dexamethasone) are administered to a patient, such as a patient in need thereof, in combination with a therapeutically effective amount of at least one additional therapeutic agent (including, but not limited to, an anticancer drug or a steroid). Such methods may also provide effective treatment for individuals with refractory cancers, including individuals currently receiving cancer treatment. Thus, in certain embodiments, the method relates to treating resistant prostate cancer in a patient, wherein a therapeutically effective amount of a 17α-hydroxylase / C17,20-lyase inhibitor is administered to a patient currently receiving an anticancer drug.

[0049] In such compositions, niraparib itself can be present in a therapeutically effective amount, abiraterone acetate itself can be present in a therapeutically effective amount, prednisone itself can be present in a therapeutically effective amount, or two or more of these conditions can be used. In other embodiments, when considered together, the total amount of niraparib, abiraterone acetate, and prednisone can represent a therapeutically effective amount, that is, the amount of niraparib itself will not be therapeutically effective, the amount of abiraterone acetate itself will not be therapeutically effective, and the amount of prednisone itself will not be therapeutically effective. For the purposes of the compositions of the present invention, a "therapeutically effective amount" is defined as described above in conjunction with the methods of the present invention.

[0050] The composition containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

[0051] Compositions intended for oral administration may be prepared according to any method known in the art for making pharmaceutical compositions, and in order to provide pharmaceutically high-quality and palatable preparations, such compositions may contain one or more agents selected from the following: sweeteners, flavoring agents, coloring agents and preservatives. Tablets contain active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for making tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, corn starch or alginic acid; binders such as starch, gelatin, polyvinyl-pyrrolidone or gum arabic, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract, and thereby provide sustained action over a longer period of time. For example, a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delay material such as ethylcellulose, cellulose acetate butyrate may be employed.

[0052] Formulations for oral administration may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin; or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil medium such as peanut oil, liquid paraffin or olive oil.

[0053] Aqueous suspensions contain active substances mixed with excipients suitable for making aqueous suspensions. Such excipients are suspending agents, such as sodium hydroxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxides with long-chain aliphatic alcohols such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxides with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxides with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose, saccharin or aspartame.

[0054] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oily suspensions can contain thickeners, such as beeswax, hard paraffin or cetyl alcohol sweeteners, such as those described above, and flavoring agents can be added to provide a palatable oral formulation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

[0055] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide the active ingredient mixed with a dispersant or wetting agent, a suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those mentioned above. Additional excipients, such as sweeteners, flavoring agents and coloring agents may also be present. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0056] Pharmaceutical compositions of the present invention can also be in the form of water-in-oil emulsions. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture of these. Suitable emulsifiers can be naturally occurring phosphatides, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners, flavoring agents, preservatives and antioxidants.

[0057] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain a demulcent, a preservative, flavoring and coloring agents and an antioxidant.

[0058] The pharmaceutical composition may also be in the form of a sterile aqueous solution for injection. Acceptable carriers and solvents that may be used are, for example, water, Ringer's solution and isotonic sodium chloride solution.

[0059] The sterile injection preparation can also be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient can be first dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into a mixture of water and glycerol and processed to form a microemulsion.

[0060] The injectable solution or microemulsion can be introduced into the patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in a manner that maintains a constant circulating concentration of the compound of the invention. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD- Model 5400 IV Pump.

[0061] The pharmaceutical composition can be in the form of an aqueous suspension or an oily suspension for sterile injection for intramuscular and subcutaneous administration. The suspension can be prepared according to the known art using those suitable dispersants or wetting agents and suspending agents mentioned above. The sterile injection preparation can also be a sterile injection solution or a suspension in a non-toxic parenteral acceptable diluent or solvent, for example, as a solution of 1,3-butanediol. In addition, sterile fixed oils are usually used as solvents or suspension media. For this reason, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used in injection preparations.

[0062] Compositions comprising niraparib, abiraterone acetate, and prednisone can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore dissolve in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

[0063] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the invention are employed. For the purposes of this disclosure, topical application shall include mouthwashes and gargles.

[0064] The composition comprising niraparib, abiraterone acetate and prednisone can be administered in an intranasal form via topical use of suitable intranasal carriers and delivery devices, or via a transdermal route using those forms of transdermal patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, dosage administration will of course be continuous rather than intermittent throughout the dosage regimen.

[0065] When a composition comprising niraparib, abiraterone acetate, and prednisone is administered to a patient, the selected dosage level of each drug will depend on a variety of factors, including, but not limited to, the activity of the particular compound, the severity of the individual's symptoms, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, and / or substances used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of niraparib, the amount of abiraterone acetate, and the amount of prednisone and the route of administration will ultimately be at the discretion of the physician, but generally the dosage will be such that the local concentration at the site of action achieves the desired effect without causing substantial harm or adverse side effects.

[0066] The composition may include, for example, about 100 mg to about 350 mg of niraparib, about 100 mg to about 1500 mg of abiraterone acetate, and about 2 mg to about 15 mg of prednisone.

[0067] For example, the compositions of the invention can include niraparib in an amount of, for example, 100 mg to about 350 mg, about 100 mg to about 340 mg, about 125 mg to about 340 mg, about 150 mg to about 325 mg, about 175 mg to about 325 mg, about 200 mg to about 300 mg, or can be about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg.

[0068] The compositions of the present invention may also include abiraterone acetate in an amount of, for example, about 100 mg to about 1500 mg, about 125 mg to about 1400 mg, about 150 mg to about 1300 mg, about 175 mg to about 1200 mg, about 200 mg to about 1175 mg, about 225 mg to about 1150 mg, about 250 mg to about 1100 mg, about 250 mg to about 1075 mg, about 250 mg to about 1050 mg, about 250 mg to about 1000 mg, about 300 mg to about 950 mg, about 350 mg to about 900 mg, about 400 mg to about 850 mg, about 450 mg to about 800 mg, or about 500 mg to about 700 mg, or may be about 100 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, or about 1500 mg.

[0069] The compositions of the present invention may also include prednisone in an amount of, for example, about 2 mg to about 15 mg, about 2 mg to about 14 mg, about 3 mg to about 13 mg, about 4 mg to about 12 mg, about 5 mg to about 11 mg, about 5 mg to about 10 mg, about 6 mg to about 11 mg, about 7 mg to about 11 mg, about 8 mg to about 11 mg, about 9 mg to about 11 mg, or may be about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg.

[0070] Also disclosed herein is a kit comprising a composition comprising niraparib, a composition comprising abiraterone acetate, a composition comprising prednisone, and instructions for administering the composition to a human patient suffering from prostate cancer. The instructions may provide instructions for administering the corresponding composition once a day, twice a day, or multiple times a day. For example, the instructions may provide instructions for administering a composition comprising niraparib and a composition comprising abiraterone acetate once a day to a human patient suffering from prostate cancer, and for administering a composition comprising prednisone twice a day to the human patient.

[0071] In the kit of the present invention, the composition comprising niraparib, the composition comprising abiraterone acetate, and the composition comprising prednisone may represent separate compositions, or two or more of the composition comprising niraparib, the composition comprising abiraterone acetate, and the composition comprising prednisone may be one and the same. In other words, in the latter case, the kit of the present invention comprises a composition according to the present disclosure, which comprises two or all of niraparib, abiraterone acetate, and prednisone as described above. Regardless of whether the composition comprising niraparib, the composition comprising abiraterone acetate, and the composition comprising prednisone represent separate compositions, respectively, the corresponding composition may have the characteristics of the pharmaceutical composition of the present invention described above. Therefore, one or more compositions in the kit of the present invention can be constructed for any desired route of administration and contain any excipients, additives and a certain amount of corresponding drugs according to the aforementioned description. For example, according to the aforementioned description involving the composition of the present invention, the corresponding composition may contain, for example, about 100 mg to about 350 mg of niraparib, about 100 mg to about 1500 mg of abiraterone acetate and about 2 mg to about 15 mg of prednisone (or any combination of these).

[0072] In some cases, the composition comprising abiraterone acetate is a dosage form (i.e., an oral dosage form) configured for oral administration to a patient, the composition comprising prednisone is a dosage form configured for oral administration to a patient, and the composition comprising niraparib is a dosage form configured for oral administration to a patient, and the kit includes two to five dosage forms comprising abiraterone acetate for each dosage form comprising niraparib, and one to three dosage forms comprising prednisone for each dosage form comprising niraparib. Therefore, the expected administration regimen of such a kit is to administer a dosage form comprising niraparib for every two to five dosage forms comprising abiraterone acetate and every one to three dosage forms comprising prednisone administered to a patient. For example, a once-daily administration associated with such a kit may include administering a single dosage form such as a capsule comprising niraparib, two to five dosage forms comprising abiraterone acetate, and one to three dosage forms comprising prednisone. In such cases, the respective dosage forms comprising abiraterone acetate and prednisone may individually contain less abiraterone acetate and prednisone than would provide a therapeutically effective dose, but since they are intended to be taken in groups of two to five or one to three, respectively, the combination of two to five or one to three dosage forms will represent a therapeutically effective amount of abiraterone acetate and prednisone, respectively. In one embodiment, administration associated with the kit of the invention comprises administration of a single dosage form comprising niraparib, four dosage forms comprising abiraterone acetate, and two dosage forms comprising prednisone.

[0073] In some cases, one or more of niraparib, abiraterone acetate, and prednisone is administered in a multiple-times-a-day regimen, and the other one or both of niraparib, abiraterone acetate, and prednisone is administered once a day. For example, niraparib and abiraterone acetate may be administered once a day, while prednisone is administered two or three times a day. One embodiment involves administering niraparib and abiraterone acetate once a day and administering prednisone twice a day. In a specific embodiment, administration associated with the kit of the invention comprises administration of a single dosage form comprising niraparib, four dosage forms comprising abiraterone acetate, and two dosage forms comprising prednisone, wherein niraparib and abiraterone acetate are administered once daily (i.e., each individual dosage form is administered together once), and prednisone is administered twice daily (i.e., one dosage form comprising prednisone is administered at a particular time point during a day, and the second dosage form comprising prednisone is administered at a later time point during a day, such as four hours, five hours, six hours, seven hours, eight hours, nine hours, 10 hours, 11 hours, or 12 hours later).

[0074] Depending on which of the foregoing administration regimens or another regimen is employed, the instructions will provide appropriate guidance for administering one or more compositions included in the kit once daily.

[0075] The following examples further define the present invention. It should be understood that these examples, although indicating preferred embodiments of the present invention, are given by way of illustration only and should not be construed as limiting the appended claims. Based on the above discussion and these examples, those skilled in the art can ascertain the essential characteristics of the present invention, and without departing from the spirit and scope of the present invention, various changes and modifications may be made to the present invention to adapt it to various uses and conditions.

[0076] Example

[0077] Example 1 - Combination Therapy with Patient Evaluation

[0078] Niraparib is provided as 200mg capsules or tablets, and patients are orally administered once a day, abiraterone acetate is provided as capsules or tablets (4×250mg, total dose 1000mg), and is orally administered once a day, and prednisone is provided as tablets or capsules (2×5mg), and is orally administered twice a day (5mg per tablet, twice a day). The dose of niraparib is taken at a starting dose of 200mg once a day, which is 67% of the current clinical dose of niraparib monotherapy. The dose of abiraterone acetate 1000mg once a day remains unchanged throughout the treatment period, and the dose of prednisone 5mg twice a day also remains unchanged during the treatment period. Starting from the first day of the first cycle, all drugs are administered together. The drug must be swallowed as a whole. Patients take their doses in the morning (with or without food), except for the days when pharmacokinetic (PK) sampling occurs. Allow water. A snack (e.g., crackers, cheese, and juice) was provided 2 hours after PK blood sample collection, a standard lunch (e.g., a turkey submarine sandwich with cheese, lettuce, tomato, and sauce, plus a cup of tea or coffee) was provided 4 hours after PK blood sample collection, and a standard dinner (e.g., chicken, broccoli, and rice, plus 1 cup of tea or coffee) was provided 8 hours after PK blood sample collection.

[0079] Pharmacokinetic evaluation. According to the time and event schedule for PK and pharmacodynamic evaluation, blood samples were collected within the 24-hour dosing interval on Day 28 of Cycle 1. Plasma levels of niraparib and its major metabolite (M1), and abiraterone acetate and its active metabolite abiraterone, were measured, together with plasma levels of prednisone. The following steady-state key PK parameters were calculated for niraparib, abiraterone acetate, and prednisone.

[0080] Evaluation of anti-tumor activity. Evaluation of anti-tumor activity includes the following:

[0081] Tumor measurements: CT or MRI scan of the chest, abdomen, and pelvis and whole-body bone scan ( 99m Tc),

[0082] Serum prostate-specific antigen (PSA) Survival status

[0083] ·CTC SSE

[0084] Prostate-specific antigen (PSA) evaluation was performed by applying Prostate Cancer Working Group 3 (PCWG3) recommendations. During the treatment phase, radionuclide bone scan or CT / MRI imaging evaluation was optionally performed at the discretion of the investigator according to institutional guidance in the event of observed PSA progression or suspected clinical progression.

[0085] All enrolled subjects will be analyzed. Antitumor activity evaluation will be performed. PSA evaluation and bone development evaluation will be based on PCWG3 recommendations, and soft tissue (visceral and / or nodal disease) evaluation will be based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

[0086] Antitumor activity was analyzed as follows:

[0087] PSA decline at 12 weeks: Percent change (increase or decrease) from baseline in PSA at 12 weeks using a waterfall plot.

[0088] Maximum PSA drop: The largest change (up or down) at any time using a waterfall chart.

[0089] At 8 weeks after baseline, CTC response was defined as CTC=0 per 7.5 mL of blood.

[0090] Objective response rate (ORR) of soft tissue (visceral and / or nodal disease) without significant bone progression as defined by RECIST version 1.1 according to PCWG3 criteria.

[0091] Analysis of response rates will be tabulated and their two-sided 95% exact confidence intervals will also be presented.

[0092] Antitumor evaluations were performed as specified in the Time and Event Schedules 1 and 2. Unscheduled evaluations should be considered if clinically indicated and the results collected in the eCRF. Evaluations of antitumor activity included the following:

[0093] Tumor measurements: CT or MRI scan of the chest, abdomen, and pelvis and whole-body bone scan ( 99m Tc). The same imaging modality should be used throughout the evaluation of an individual subject. Imaging will be assessed by the investigator. After the first documented response or progression, repeat imaging will be required approximately 4 weeks later for confirmation.

[0094] Serum PSA survival status

[0095] CTC symptomatic skeletal events (SSE)

[0096] Evaluation of treatment response by PSA, imaging, and CTC will be performed according to PCWG3 criteria. SSE should be evaluated according to PCWG3 criteria. Tumor assessment and PSA development should be evaluated according to PCWG3.

[0097] Pharmacodynamics. Blood samples were collected for isolation of peripheral blood mononuclear cells (PBMCs). Lysates of peripheral blood mononuclear cells (PBMCs) were used to quantify poly-ADP-ribose in PBMCs by chemiluminescent enzyme-linked immunosorbent assay.

[0098] Biomarker Evaluation. All patients had tumor tissue (archive or recently collected) and blood samples collected during the Screening Phase for definitive biomarker analysis; the results did not determine eligibility.

[0099] Biomarker-positive samples for DNA repair abnormalities

[0100] To evaluate whether a patient is biomarker positive, a blood-based assay may become available during the study, which will provide a more rapid method to determine biomarker positive status than tissue-based analysis while being more convenient for the patient. Tumor tissue (archived or recently collected) will need to be analyzed before blood-based assays become available. To ensure that all patients (regardless of when they enter the study) have the same biomarker data available for analysis (i.e., for consistency and bridging studies), both tumor tissue and blood samples will be collected from all patients who sign the prescreening informed consent form (ICF). The process for determining biomarker positivity for patients who enter the prescreening phase before the blood-based assay is available will be different than for those patients who enter after the blood-based assay is available. However, all patients will be assessed for biomarker positive status for both tumor tissue and blood.

[0101] To be eligible for the study, patients must have confirmed biomarker positivity by tumor tissue (archive or recently collected) or blood testing (when available). The biomarkers of interest for this study and the criteria for biomarker positivity are listed in Table 1. Analyses will be performed to define biallelic loss (e.g., mutation co-expression frequency, with copy number loss) surrogate indicators, and these surrogate indicators can be used to determine biomarker positivity when this information becomes available.

[0102] Table 1: Biomarker Panels and Positive Criteria

[0103]

[0104] Monoallelic losses in all genes will be acceptable for entry into the study until existing algorithms for biallelic losses are validated.

[0105] Circulating tumor cells

[0106] Blood samples were collected in blood sample storage tubes at the time points specified in the time and event schedule. CTC counts were evaluated in a central laboratory to assess the response to study drug.

[0107] Whole Blood for RNA

[0108] Whole blood samples will be collected in Paxgene tubes. Multiple ribonucleic acid (RNA) transcripts present in prostate tumors are detectable in RNA, and analysis of these samples will allow evaluation of potential resistance mechanisms that may arise from niraparib.

[0109] Circulating tumor DNA

[0110] Plasma samples collected during the course of treatment will be screened for changes in the levels or types of DNA repair abnormalities observed through circulating tumor DNA (ctDNA) over time and to monitor potential markers of niraparib resistance.

[0111] All subjects will have tumor tissue (archived or recently collected) and blood samples collected during the screening phase for determination of biomarker analysis; results will not determine eligibility. Evaluation of associations between biomarkers and anti-tumor activity may be performed. Concordance of genomic alterations between tumor DNA and circulating tumor DNA may also be assessed. Circulating tumor cell (CTC) response to study drug will be evaluated.

[0112] Safety Evaluations. Safety assessments were based on medical review of adverse event reports and results of vital sign measurements, electrocardiogram (12-lead), physical examination, clinical laboratory tests, and Eastern Cooperative Oncology Group performance status.

[0113] Pharmacokinetic and pharmacokinetic / pharmacodynamic analysis. Individual and mean plasma concentration-time data were summarized with descriptive statistics, and the concentration-time distributions of niraparib and its major metabolite (M1) and abiraterone acetate and its active metabolite (abiraterone) were plotted. PK parameters were summarized with descriptive statistics. The relationship between niraparib, abiraterone acetate, prednisone and pharmacodynamic or clinical activity or safety endpoints was optionally evaluated.

[0114] Analysis of antitumor activity. Patients were analyzed for antitumor activity. PSA evaluation was based on PCWG3 recommendations and the following conditions: PSA response rate: a decrease of ≥50% from baseline during the study and confirmed by a second measurement 3 to 4 weeks later; PSA response at 12 weeks: the percentage change (increase or decrease) from baseline in PSA at 12 weeks using a waterfall plot; Maximum PSA decrease ≥50%: the maximum change (increase or decrease) at any time using a waterfall plot.

[0115] Safety Analysis. Safety parameters evaluated were the incidence, intensity, and type of adverse events, vital sign measurements, ECG, physical examination (abnormalities will be recorded as adverse events), ECOGPs, and clinical laboratory results.

[0116] Example 2 - Effect of Niraparib plus Abiraterone on a human prostate tumor model implanted in castrated male mice Efficacy of (VCaP)

[0117] Objective: This study evaluated the efficacy of niraparib in combination with abiraterone in castrated male mice bearing human VCaP prostate tumors. Readouts were tumor volume and survival.

[0118] Cell culture

[0119] The human VCaP prostate tumor line was derived from a spinal metastasis of a patient with castration-resistant prostate cancer. VCaP tumor cells carry a TMPRSS2-ERG fusion and express the androgen receptor. The VCaP tumor cell line was maintained in DMEM medium supplemented with 10% fetal bovine serum in an atmosphere of 5% CO2 in air at 37C. Tumor cells were subcultured twice a week by trypsin-EDTA treatment. Cells were harvested for tumor injection when they were in the exponential growth phase.

[0120] Tumor cell injection and study design

[0121] Each mouse was injected subcutaneously in the right flank with 0.1 ml of Matrigel-containing PBS (1:1) containing VCaP tumor cells (1×10 7 ) to allow tumor development. The date of tumor cell inoculation is denoted as day 0. Mice were assigned to treatment groups to ensure that the average tumor size was approximately 200 mm 3 , and now all mice are castrated.As shown in the table 2 of test article administration and animal numbering in each group, treatment is started 1 day after castration.The grouping date before treatment starts is expressed as grouping after 0 day (PG-D0).Continue to administer for 35 days (the 57th day), and monitor the tumor volume of mice during administration, and until each mouse arrives the research end point.When the tumor volume reaches 1500mm 3 When , the mice were euthanized.

[0122] Tumor volume was measured twice a week using calipers in two dimensions and using the formula: V = 0.5a x b 2 In mm 3 Expressed as volume, where a and b are the length and width of the tumor, respectively.

[0123] Table 2: Study design

[0124]

[0125] Note:

[0126] 1. N: number of animals;

[0127] 2. Dose volume: Adjust based on body weight (10 μL / g).

[0128] 3. Administer abiraterone first, followed by niraparib 7 to 8 hours later.

[0129] Data statistics and analysis

[0130] All data were plotted and certain calculations performed, including median life span, survival, and tumor volume, using Prism (GraphPad version 7). Survival data were evaluated using the log-rank Mantel-Cox test.

[0131] Tumor growth inhibition (TGI) was calculated as follows: TGI (%) = 100 x (1-T / C). T and C are the average tumor volumes of the treatment group and the control group, respectively, on a given day.

[0132] A p value of < 0.05 was considered significant.

[0133] result

[0134] Each treatment inhibited tumor growth during the dosing period from Days 23 to 57 when compared to vehicle control ( Figure 1 ). When compared to the vehicle control, niraparib inhibited tumor growth by approximately 25% from day 41 to day 55. When compared to the control group, abiraterone showed greater inhibition of tumor growth from day 37 to day 55 (range 35% to 46%). When compared to the vehicle control group, the combination of niraparib and abiraterone showed the most significant inhibition of tumor growth from day 37 to day 55 (range 38% to 58%).

[0135] Tumor growth inhibition (TGI) at day 58 is calculated in Table 3 and shows that each treatment significantly reduced tumor growth compared to the control group. These results show that niraparib or abiraterone as a single agent can inhibit the growth of VCaP tumors, but the combination of niraparib / abiraterone is the most effective in inhibiting tumor growth.

[0136] Table 3: Antitumor activity of test compounds evaluated by tumor growth inhibition assay

[0137]

[0138] Note: a: mean ± SEM; b, c: comparison with vehicle control. TGI, tumor growth inhibition.

[0139] Survival curves and statistics are shown in Figure 2and Table 4. The vehicle control group showed an MLS of 77.5 days (Table 3). Niraparib did not prolong the MLS or provide a significant beneficial effect on survival only when compared to the vehicle control group. Abiraterone alone extended the MLS by 10.5 days and significantly prolonged survival compared to the vehicle control group (p=0.0192). Compared with the vehicle control group, the combination group of niraparib / abiraterone showed the greatest effect on survival, with an MLS of 105.5 days and a significant prolongation of survival (p<0.0001). Niraparib / abiraterone treatment also significantly prolonged survival compared to single drugs niraparib (p<0.0001) and abiraterone (p=0.0021).

[0140] These results suggest that niraparib or abiraterone as single agents significantly prolonged survival in mice with VCaP tumors, but the niraparib / abiraterone combination was most effective for prolonging survival.

[0141] Table 4: Effect of niraparib and / or abiraterone on the survival of tumor-bearing mice

[0142]

[0143] Note: a: MLS, median life span (survival range). b: Log-rank test was used to determine the difference between each treatment group and the vehicle control.

[0144] p-value for survival compared between groups. ILS, extended lifespan; compared with group 1.

[0145] While the above description illustrates the principles of the invention by providing embodiments thereof, it should be understood that the practice of the invention encompasses all general variations, changes and / or modifications within the scope of the following claims and their equivalents.

[0146] The present application relates to the following embodiments.

[0147] 1. A method for treating prostate cancer, comprising administering to a patient in need thereof a therapeutically effective amount of niraparib, a therapeutically effective amount of abiraterone acetate, and a therapeutically effective amount of prednisone.

[0148] 2. A method according to embodiment 1, wherein the prostate cancer is hormone-sensitive or castration-resistant prostate cancer.

[0149] 3. The method according to embodiment 2, wherein niraparib and abiraterone acetate are administered to the patient as a single composition.

[0150] 4. The method of embodiment 2, wherein niraparib is administered in a separate composition than abiraterone acetate.

[0151] 5. The method according to embodiment 1, wherein niraparib and abiraterone acetate are each administered to the patient once a day.

[0152] 6. The method according to any one of embodiments 1, wherein niraparib is administered in a separate composition different from the abiraterone acetate and prednisone.

[0153] 7. The method according to any one of embodiments 1, wherein niraparib, abiraterone acetate, and prednisone are each administered as separate compositions.

[0154] 8. The method of embodiment 2, comprising administering to the patient about 500 mg / day to about 1500 mg / day of the abiraterone acetate.

[0155] 9. The method of embodiment 8, comprising administering to the patient about 600 mg / day to about 1300 mg / day of the abiraterone acetate.

[0156] 10. The method of embodiment 9, comprising administering to the patient about 900 mg / day to about 1100 mg / day of the abiraterone acetate.

[0157] 11. The method of embodiment 10, comprising administering about 1000 mg / day of the abiraterone acetate to the patient.

[0158] 12. The method of embodiment 11, comprising administering about 500 mg / day of the abiraterone acetate to the patient.

[0159] 13. The method of embodiment 8, comprising administering to the patient about 30 mg / day to about 400 mg / day of niraparib.

[0160] 14. The method of embodiment 13, comprising administering to the patient about 100 mg / day to about

[0161] 300 mg / day of the niraparib.

[0162] 15. The method of embodiment 14, comprising administering to the patient about 175 mg / day to about 225 mg / day of the niraparib.

[0163] 16. The method of embodiment 11, comprising administering about 200 mg / day of niraparib to the patient.

[0164] 17. The method of embodiment 12, comprising administering about 200 mg / day of niraparib to the patient.

[0165] 18. The method of embodiment 13, comprising administering to said patient from about 1 mg / day to about 25 mg / day of said prednisone.

[0166] 19. The method of embodiment 14, comprising administering to said patient about 5 mg / day to about 15 mg / day of said prednisone.

[0167] 20. The method of embodiment 15, comprising administering to said patient from about 9 mg / day to about 11 mg / day of said prednisone.

[0168] 21. The method of embodiment 16, comprising administering about 10 mg / day of said prednisone to said patient.

[0169] 22. The method of embodiment 17, comprising administering about 10 mg / day of said prednisone to said patient.

[0170] 23. The method of embodiment 16, comprising administering about 5 mg / day of said prednisone to said patient.

[0171] 24. The method of embodiment 17, comprising administering about 5 mg / day of said prednisone to said patient.

[0172] 25. The method according to embodiment 1, comprising administering the niraparib and the abiraterone acetate to the patient once a day for multiple days, and increasing the dose of one or both of the niraparib and abiraterone acetate at least once over time.

[0173] 26. The method of embodiment 5, wherein the dose of niraparib is increased at least once over time.

[0174] 27. The method of embodiment 25, comprising administering the prednisone to the patient twice daily for multiple days, and increasing the dose of the prednisone at least once over time.

[0175] 28. The method according to embodiment 1, comprising orally administering the niraparib, the abiraterone acetate, and the prednisone to the patient.

[0176] 29. The method according to any preceding embodiment 1, wherein the patient has received taxane-based chemotherapy prior to administration of the first dose of the niraparib and the abiraterone acetate.

[0177] 30. The method according to embodiment 1, wherein the patient is administered niraparib and

[0178] The patients had received at least one line of androgen receptor targeted therapy before the first dose of abiraterone acetate.

[0179] 31. A pharmaceutical composition comprising niraparib, abiraterone acetate, and prednisone in a total amount therapeutically effective for treating prostate cancer in a human patient in a single oral dosage form.

[0180] 32. The composition of embodiment 1, wherein the composition is configured for oral administration.

[0181] 33. The composition of embodiment 31 or embodiment 3232, wherein the composition comprises about 100 mg to about 350 mg of the niraparib, about 100 mg to about 1500 mg of the abiraterone acetate, and about 2 mg to about 15 mg of the prednisone.

[0182] 34. A pharmaceutical composition comprising niraparib, abiraterone acetate, and prednisone in a total amount therapeutically effective for treating prostate cancer in a human patient in multiple oral dosage forms.

[0183] 35. The composition of embodiment 33, wherein the composition is configured for oral administration.

[0184] 36. The composition of embodiment 34 or embodiment 35, wherein the composition comprises about 100 mg to about 350 mg of the niraparib, about 100 mg to about 1500 mg of the abiraterone acetate, and about 2 mg to about 15 mg of the prednisone.

Claims

1. Use of a therapeutically effective amount of abiraterone acetate and a therapeutically effective amount of niraparib in the preparation of a medicament for treating metastatic prostate cancer for administration to a patient in need thereof, wherein the patient has a DNA repair abnormality.

2. The use according to claim 1, wherein the patient has a DNA repair abnormality in at least one gene selected from BRCA-1 and BRCA-2.

3. The use according to claim 1 or 2, wherein the prostate cancer is hormone-sensitive or castration-resistant prostate cancer.

4. The use according to any one of claims 1 to 3, wherein niraparib and abiraterone acetate are administered to the patient in a single composition.

5. The use according to any one of claims 1 to 3, wherein niraparib is administered in a separate composition from abiraterone acetate.

6. The use according to any one of the preceding claims, wherein niraparib and abiraterone acetate are each administered once a day to the patient.

7. The use according to any one of the preceding claims, wherein niraparib and abiraterone acetate are administered together with prednisone or prednisolone.

8. The use according to claim 7, wherein niraparib is administered in a separate composition different from the abiraterone acetate and the prednisone or prednisolone.

9. The use according to any one of the preceding claims, wherein about 500 to about 1500 mg / day of the abiraterone acetate is administered to the patient.

10. The use according to claim 9, wherein about 600 to about 1300 mg / day of the abiraterone acetate is administered to the patient.

11. The use of claim 9, wherein about 900 to about 1100 mg / day of the abiraterone acetate is administered to the patient.

12. The use according to claim 11, wherein about 1000 mg / day of said abiraterone acetate is administered to said patient.

13. The use according to claim 12, wherein about 500 mg / day of said abiraterone acetate is administered to said patient.

14. The use according to claim 9, wherein about 30 to about 400 mg / day of the niraparib is administered to the patient.

15. The use according to claim 14, wherein about 300 mg / day of said niraparib is administered to said patient.

16. The use according to claim 14, wherein about 200 mg / day of the niraparib is administered to the patient.

17. The use according to claim 14, wherein about 100 mg / day of the niraparib is administered to the patient.

18. The use according to claim 14, wherein about 50 mg / day of the niraparib is administered to the patient.

19. The use according to claim 7, wherein about 1 to about 25 mg / day of said prednisone or prednisolone is administered to said patient.

20. The use according to claim 19, wherein about 5 to about 15 mg / day of said prednisone or prednisolone is administered to said patient.

21. The use of claim 19, wherein about 9 to about 11 mg / day of said prednisone or prednisolone is administered to said patient.

22. The use of claim 19, wherein about 10 mg / day of said prednisone or prednisolone is administered to said patient.

23. The use of claim 19, wherein about 5 mg / day of said prednisone or prednisolone is administered to said patient.

24. The use according to any one of the preceding claims, wherein the niraparib and the abiraterone acetate are to be administered orally to the patient.

25. The use according to any one of the preceding claims, wherein the patient has received taxane-based chemotherapy prior to administration of the first dose of the niraparib and the abiraterone acetate.

26. The use according to any one of the preceding claims, wherein the patient has received at least one line of androgen receptor targeted therapy prior to administration of the first dose of niraparib and abiraterone acetate.

27. The use according to any one of the preceding claims, wherein the niraparib is niraparib p-toluenesulfonate including niraparib p-toluenesulfonate monohydrate, niraparib chloride, niraparib trifluoroacetate, niraparib sulfate, niraparib besylate, niraparib fumarate or niraparib succinate.

28. The use according to any one of the preceding claims, wherein the niraparib is (3S)-3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}piperidinium 4-methylbenzenesulfonate monohydrate.

29. A pharmaceutical composition comprising niraparib and abiraterone acetate in a total amount therapeutically effective for treating metastatic prostate cancer in a human patient with a DNA repair abnormality in a single oral dosage form.

30. The pharmaceutical composition according to claim 29, wherein the patient has a DNA repair abnormality in at least one gene selected from BRCA-1 and BRCA-2.

31. The composition of claim 29 or 30, wherein the composition is configured for oral administration.

32. The composition of any one of claims 29-31, wherein the composition comprises about 30 to about 400 mg of the niraparib and about 500 to about 1000 mg of the abiraterone acetate.

33. The composition of any one of claims 29-32, wherein the composition further comprises prednisone or prednisolone.

34. The composition of claim 33, wherein the composition comprises from about 2 to about 15 mg of prednisone or prednisolone.

35. The composition of claim 33 or 34, wherein the composition comprises about 5 or 10 mg of prednisone or prednisolone.

36. A pharmaceutical composition comprising niraparib and abiraterone acetate in a total amount therapeutically effective for treating metastatic prostate cancer in a human patient with a DNA repair abnormality in multiple oral dosage forms.

37. The pharmaceutical composition according to claim 36, wherein the patient has a DNA repair abnormality in at least one gene selected from BRCA-1 and BRCA-2.

38. The composition of claim 36 or 37, wherein the composition is configured for oral administration.

39. The composition of claims 36-38, wherein the composition comprises about 30 to about 400 mg of the niraparib and about 500 to about 1000 mg of the abiraterone acetate.

40. The composition of any one of claims 36-39, wherein the composition further comprises prednisone or prednisolone.

41. The composition of claim 40, wherein the composition comprises from about 2 to about 15 mg of prednisone or prednisolone.

42. The composition of claim 40 or 41, wherein the composition comprises about 5 or 10 mg of prednisone or prednisolone.

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